Does Medicalization of Life Imperil Health? Expanding Indications for Diagnosis and Treatment of Chronic “Disease”

A 2010 Wall Street Journal (WSJ) report highlighted a novel training method now being used by medical schools to “help budding psychologists and psychiatrists gain experience and confidence” in differential diagnosis—assessment of fictional characters. Popular movies and books have provided rich fare for the trainees. Southern vamp Scarlett O’Hara has narcissistic personality disorder. Harry Potter’s “battle with Voldemort can be seen as an internal conflict between aspects of his own psyche.” HBO gangster Tony Soprano has panic attacks and depression. And Winnie the Pooh, the “bear of little brain” with a seemingly never-ending penchant for “hunney,” has a cognitive impairment disorder coupled with obsession. The WSJ assessment of Pooh was not the first of its kind. In 2000, Pooh had been described in a tongue-in-cheek CMAJ commentary as having attention-deficit hyperactivity disorder (ADHD), inattentive subtype, possibly the result of “being dragged downstairs bump, bump, bump,on the back of his head” according to an early account by Pooh’s creator, A. A. Milne, perhaps leading to “Shaken Bear Syndrome. Although the spoof was witty, health care payers and the enrollees they serve may have less reason to be amused. Research published within the past few years suggests an explosion in the medicalization and treatment of…

expanded dyslipidemia "disease" prevalence to 73% of U.S. adults and 84% of adults aged 60 years or older, according to the analysis by Kaplan and Ong. 4 Reduction in the threshold definition of impaired fasting glucose (IFG) from 110 mg per dL to 100 mg per dL by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (ECDCDM) in 2003 10 increased estimated IFG/diabetes prevalence to 37% of U.S. adults aged 50 years or older. 4 Kaplan and Ong estimated that applying all 3 expanded diagnostic criteria to the U.S. population would qualify a staggering 97% of adults aged 50 years or older for a diagnosis of at least 1 of the 3 chronic conditions. 4

Expansion in the Number of Persons with Mental Illness: APSS
Diagnostic expansions are not limited to cardiovascular disease biomarkers. A June 2011 Carlat Psychiatry Report interview with psychiatrist William Carpenter, a member of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 work group, examined the possibility that a new psychiatric diagnosis, "attenuated psychosis syndrome" or "attenuated psychotic symptoms syndrome" (APSS), will be included in the 2013 release of the DSM-5. 11,12 The diagnosis is currently undergoing field trials with clinicians and will likely be defined as a psychiatric disorder and given a new diagnosis code if clinical reliability rates are approximately 0.6-0.7 or higher, according to Carpenter. 11 An APSS label might be applied to somebody, probably an adolescent or young adult, who has "some psychotic-like symptoms" but without "sufficient severity to make a psychosis diagnosis" in the judgment of the clinician. 11 Formally, the diagnosis would be made if "at least [1] of [3] attenuated positive psychotic symptoms, including delusions, hallucinations, and disorganized speech" were "present with reality testing intact" at "a specified frequency … and duration," coupled with distress and disability sufficient to prompt the patient and/or parent or guardian to "seek help." 12 Initially described as a "risk syndrome for first psychosis," the syndrome was renamed APSS after concerns were raised about "false positives," that is, the large proportion of those meeting the criteria for the disorder who would not go on to develop full-blown psychosis. Proponents argue that preventing mental illness through early detection and treatment "parallels the [preventive] strategies that have been applied to many chronic physical illnesses." 12 Detractors observe that the highest reported progression rates to psychosis are approximately 40%-50%, and more recent studies suggest an even lower progression rate of approximately 10%-20%, potentially resulting in a high rate of false-positive mental illness disease labeling with "life altering stigma" and effects on educational and career choices. 12 Nonetheless, a 2010 meta-analysis of data from the Emerging Risk Factors Collaboration group provided empirical support for the decision that had been made by the ECDCDM 7 years previously. 13 In 698,782 study subjects totaling 8.49 million person-years at risk in 102 prospective studies, a nonlinear relationship between fasting blood glucose (FBG) and incident coronary heart disease (CHD) was noted, with risk beginning to increase at approximately the threshold specified by the ECDCDM. Specifically, among those without known diabetes at baseline (n = 260,361), no significant associations between FBG and CHD were noted for FBG levels from 70 to 100 mg per dL (reported as 3.90 millimoles per liter [mmol per L] to 5.59 mmol per L). Compared with FBG of 70 to 100 mg per dL (reference group, n = 185,590), CHD incidence increased modestly with FBG levels of 101 to less than 110 mg per dL (5.60-6.09 mmol per L; hazard ratio [HR] = 1.11, 95% confidence interval [CI] = 1.04-1.18, n = 32,008) and 110 to less than 126 mg per dL (6.10-6.99 mmol per L; HR = 1.17, 95% CI = 1.08-1.26, n = 19,607). Suggesting a nonlinear relationship, CHD risk was much greater for the small group (2.8%) of subjects whose FBG was in the highest category reported, 126 mg per dL or more (7 mmol per L; HR = 1.78, 95% CI = 1.56-2.03, n = 7,240). 13

Effects of Expanded Chronic Disease Definitions on Use of Prescription Drugs
The effects of these expanded disease definitions on drug treatment recommendations are mixed and depend on baseline level of risk. Pharmacotherapy is generally not recommended as first-line treatment for patients in the new cardiovascular diagnosis groups unless additional risk factors are present. JNC-7 recommends lifestyle modifications only, including weight reduction and adoption of the dietary approaches to stop hypertension (DASH) eating plan, for those with prehypertension and without the "compelling indications," diabetes and/or chronic kidney disease. 5 Similarly, for patients without CHD and with 0 (zero) or 1 "risk equivalents" (cigarette smoking, hypertension, high-density lipoprotein cholesterol [HDL-C] < 40 mg per dL, history of CHD in a male relative prior to age 55 years or a female relative prior to age 65 years, and patient age ≥ 45 years for men or ≥ 55 years for women), ATP-III guidelines recommend therapeutic lifestyle changes with drug therapy "optional" if LDL-C is 160 mg per dL or higher and drug therapy if LDL-C is 190 mg per dL or higher. 8 However, for patients with diagnosed CHD or with a 10-year CHD risk greater than 20% by Framingham score, the 2004 update to ATP III guidelines decreased the LDL-C pharmacotherapy trigger level from 130 mg per dL to 100 mg per dL and suggested that for patients at "very high" risk with a baseline LDL-C of less than 100 mg per dL, an LDL-C goal of less than 70 mg per dL is a "reasonable clinical strategy." 9 In the original (2001) ATP III guidelines for this group, drug therapy was considered "optional" for LDL-C of 100 to 129 mg per dL. 8,9 For those at "moderately high" risk (2 or more risk factors and 10-year CHD risk 10%-20% by Framingham score), the 2004 update noted that "the recommended LDL-C goal is < 130 [mg per dL], but an LDL-C goal < 100 [mg per dL] is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately-high risk persons with a baseline LDL-C of 100 to 129 [mg per dL])." 9 The effect of the IFG threshold reduction on use of antidiabetic drugs is unknown. In a commentary published 1 month following the ECDCDM change in the definition of IFG, Davidson et al. argued that the most likely impact of the decision would be an increase in the number of people attempting lifestyle change because "almost all individuals with IFG will have other risk factors of the Insulin Resistance Syndrome … and will require treatment for these regardless of their [fasting plasma glucose] concentration." 14 However, Davidson et al. observed that "there are certainly no data to suggest that this would happen and, given the difficulty of convincing patients with known diabetes to undergo such lifestyle changes, it seems very unlikely that this will occur in the larger number of individuals who are now told that they have IFG." 14 Yet, in a conundrum familiar to most managed care decision makers, even when treatment guidelines recommend lifestyle change prior to initiating pharmacotherapy, whether those recommendations will be followed by patients and providers is hard to say. Kaplan and Ong argued that expanded definitions of "disease" are likely to lead to increased use of prescription drugs regardless of guideline recommendations, in part because of the influence of direct-to-consumer advertising. 4 A similar observation was made by Allen Frances, former chair of the DSM-IV taskforce, who recently suggested that "new diagnoses are as dangerous as new drugs" because "remarkably casual procedures for defining the nature of conditions" may "lead to tens of millions being treated with drugs they may not need, and that may harm them." 3 APSS, the new diagnosis being considered for DSM-5, unfortunately may provide an example. A September 2010 commentary by Cornblatt and Correll pointed out that if adopted, the new diagnosis would be made "by busy clinicians that are not trained in the assessment of attenuated psychotic symptoms, which are defined by complicated research criteria" using standards that "have been generated entirely by specialized research clinics that use highly trained interviewers and raters whose reliability is established and constantly calibrated." 12 Cornblatt and Correll also pointed to difficulties in distinguishing "the borderline between extremes of normal teenage problems and true illness." Yet, Cornblatt and Correll suggested that real-world clinicians would likely be prompted by the diagnosis "to consider the syndrome as just a lesser form of psychosis, though this view is not supported by any solid long-term evidence," in turn possibly leading to "an unacceptably high use of medication, especially antipsychotics, which are associated with considerable and problematic cardiovascular side effects, especially in antipsychotic naïve subjects." 12 Supporting the view that increased attention to cardiovascular biomarkers contributes to growing use of prescription medications, use prevalence rates for numerous chronic therapy classes have skyrocketed in the past 10 years. For example, the year 2000 drug trend report of a major pharmacy benefits management (PBM) company reported utilization rates (claims per member per year [Rxs PMPY]) of 0.56 for antihypertensives, 0.37 for antihyperlipidemics, and 0.31 for antidiabetics. 15 One decade later, utilization rates for these therapy classes had climbed to 2.27 Rxs PMPY, 1.37 Rxs PMPY, and 0.93 Rxs PMPY, 16 respectively-representing increases of 305%, 270%, and 200% over a 10-year period. Antipsychotic use increased as well; not even included among the top 20 therapy classes (minimum 0.10 Rxs PMPY) in 2000, antipsychotic use prevalence was 0.15 Rxs PMPY in 2010. 15,16 In an analysis of IMS audit data for select therapeutic categories, Richards (2010) found that the United States ranked first among 14 countries in the utilization of atypical antipsychotics. 17

Clinical Benefits of Pharmacotherapy for Primary Prevention
In interpreting trends of this type, it is important to consider whether the increased use of pharmacotherapy that accompanies expanded disease definitions prevents progression to more advanced disease stages and, ultimately, to negative clinical outcomes, such as MI or stroke. Kaplan and Ong argued that evidence to guide this question is limited for cardiovascular biomarkers because these drugs have been tested primarily in secondary, not primary, prevention. For antihypertensive medications, notable exceptions include the TRial Of Preventing HYpertension (TROPHY) and Prevention of Hypertension with the Angiotensin-converting enzyme inhibitor RAmipril (PHARAO) randomized controlled trials (RCTs). 18 In TROPHY (2006), patients aged 30 to 65 years with prehypertension (SBP of 130-139 mm Hg and DBP of ≤ 89 mm Hg, or SBP of ≤ 139 mm Hg and DBP of 85-89 mm Hg) were randomly assigned to 2 years of treatment with candesartan 16 mg daily (n = 391) or placebo (n = 381). 19 After a mean 3.6 years follow-up (including up to 2 years of placebo treatment following 2 years of active treatment for the candesartan group), hypertension (SBP of ≥ 140 mm Hg and/or DBP of ≥ 90 mm Hg or other clinical measures of hypertension) had developed in 208 (53.2%) and 240 (63.0%) candesartan-and placebo-treated patients, respectively (P < 0.007). 19 Follow-up analysis showed no significant between-group differences on quality-of-life measures, including either the physical or mental components of the short-form (SF)-36. 20 TROPHY's methods and results have been roundly criticized in several venues, with one editorialist going so far as to call the trial "a noble effort gone sour." 18 Although noting the evidence of risk reduction with candesartan, Kaplan and Ong pointed out that TROPHY findings were inconsistent with the natural history of prehypertension. 4 In the Framingham Heart study, 4-year rates of progression from "high normal" blood pressure (130-139/85-89 mm Hg) to hypertension (140/90 mm Hg or more) were 37.3% for those younger than age 65 years and 49.5% for those aged 65 years or older-much lower than the 63% progression rate for the TROPHY placebo group. 19,21 Editorials published subsequent to the TROPHY trial pointed to its study endpoint as a key issue; instead of using a standard definition of high BP over 2-3 sequential visits, the TROPHY investigators included in the composite primary outcome an SBP of at least 140 mm Hg and/or a DBP of at least 90 mm Hg at 3 or more visits throughout the entire 4-year study period. 18,22 Although this 4-year average measure was just 1 of 4 components of the primary outcome, it contributed the majority of cases meeting the definition of progression (68.3% in the candesartan group and 70.0% in the placebo group); and between-group differences were nonsignificant on the other components (SBP of ≥ 160 mm Hg and/or DBP of ≥ 100 mm Hg at any single clinic visit; BP requiring drug treatment; SBP of ≥ 140 mm Hg and/or DBP of ≥ 90 mm Hg at month 48). 19 Another editorialist whose criticism of the trial was particularly harsh indicated that because of its "idiosyncratic primary endpoint [that] seriously impairs external applicability," as well as issues in data interpretation, the study results would "[expose] 25 million Americans to the prospect and nuisance of patienthood" and the "medical risks of unproven long term drug treatments" without evidence of benefit, suggesting that "perhaps we should humbly pause before taking on pharmacotherapy of a huge group that is even healthier than those with stage 1 hypertension where control is presently still far from ideal." 18 In PHARAO (2008), 1,008 participants aged 50 years or older with high-normal BP (SBP 130-139 mm Hg and/or DBP 85-89 mm Hg) were assigned to treatment with ramipril (n = 505) or placebo (n = 503) and followed for up to 3 years. 23 To mitigate the effects of "white coat syndrome," patients with apparent hypertension in office visit monitoring received subsequent ambulatory monitoring to confirm the diagnosis. Progression to hypertension (SBP ≥ 140 mm Hg or DPB ≥ 90 mm Hg) occurred in 155 (30.7%) of ramipril-treated patients, compared with 216 (42.9%) for placebo. No statistically significant differences in secondary endpoints, including incident cerebrovascular and cardiovascular events, or incident diabetes or other diseases, were found. Cough occurred in 4.8% and 0.4% of patients treated with ramipril and placebo, respectively. 23 Notably, the placebo progression rate in PHARAO was consistent with the natural history findings for "high normal" BP in the Framingham study, making the PHARAO results more credible than those of TROPHY. 19,21,23 Kaplan and Ong noted at the time of their review (2007) that the use of statins in patient populations without cardiovascular risk factors had not been studied. Since that time, several relevant studies of the use of statins in primary prevention have been published. These include a meta-analysis by Brugts (2008), which enrolled a patient population with elevated high-sensitivity c-reactive protein (hs-CRP), varied baseline risk levels, LDL-C less than 130 mg per dL, and no baseline cardiovascular disease. 26 In the meta-analysis by Brugts 24 The meta-analysis by Ray et al., which assessed only all-cause mortality, produced a different finding; in 65,229 study subjects followed for a total of approximately 244,000 person-years, statin treatment did not significantly reduce all-cause mortality rates (4.1% for statin vs. 4.4% for control, risk ratio = 0.91, 95% CI = 0.83-1.01). 25 In the JUPITER study over a median of 1.9 years follow-up, rates of the primary study endpoint (a composite outcome of MI, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular-related death) per 100 person-years for rosuvastatin and placebo were 0.77 and 1.36, respectively (P < 0.001); rates of all-cause mortality per 100 person-years were 1.00 and 1.25, respectively (P = 0.02); and rates of a composite outcome of MI, stroke, or cardiovascular-related death were 0.45 and 0.85, respectively (P < 0.001). 26  It is important to note that the JUPITER trial has been highly controversial for a number of good reasons. These include the possibility that early termination of the trial at a median 1.9 years of follow-up exaggerated the treatment effect; the highly selective sampling method; questions about the role of hs-CRP in cardiovascular disease; and the clinical and policy implications of treating a relatively healthy group of people with statins for several decades absent any indication of disease. 27 Unintended Consequences of Increasing "Adequate" Pain Management A 2010 editorial by rheumatologist Jonathan Graf highlighted an American societal trend toward "more attention on the treatment of pain and less on its cause" attributable to "perceived inadequacies of pain management" nationwide. 28 Examples cited by Graf include increasingly routine assessments of pain scores "along with other vital signs regardless of the nature of a patient's visit" in medical clinics; the promulgation of formal recommendations for pain management by high-profile organizations including the American College of Rheumatology and the American Society of the Interventional Pain Physicians; and even legislative mandates. Among these was a 1997 California law, dubbed the "Pain Patient's Bill of Rights," stating that because "for some patients, pain management is the single most important treatment a physician can provide," a patient who "suffers from severe chronic intractable pain has the option to choose opiate medications to relieve severe chronic intractable pain without first having to submit to an invasive medical procedure." 29 Not surprisingly given the societal trend, the use prevalence rate for narcotic pain medications has increased dramatically in the past decade in the United States-nearly doubling from 0.41 in 2000 to 0.78 in 2010, according to PBM data. 15 40 The most commonly used therapy classes included drugs to treat asthma (45.4 million prescriptions), ADHD (24.4 million), antidepressants (9.6 million, of which 11% were dispensed to children younger than 10 years), antipsychotics (6.5 million, 21% dispensed to children younger than 10 years), and antihypertensives (5.2 million). The report found that more than 25% of U.S. children and adolescents take at least 1 prescription drug on a regular basis.
Although not peer-reviewed, the WSJ report is consistent with peer-reviewed studies of prescribing trends in children and adolescents.  42 In a large PBM database of pharmacy claims for U.S. children aged 6 to 18 years, Liberman et al. found declines of 14%-20% for dyslipidemia medications, depending on age/sex category, but marked increases in use prevalence for other chronic pharmacotherapies, including metformin (+ 24.9%), insulin (+ 14.8%), insulin combined with oral antidiabetic drugs (+ 23.3%), angiotensin-converting enzyme (ACE) inhibitors (+ 27.7% for girls, + 25.2% for boys), and beta-blockers (+ 3.0% for girls, + 7.0% for boys). From April through July 2007, use prevalence rates per 1,000 were 1.878 for antidiabetics overall, 0.456 for oral antidiabetics, 1.486 for antihypertensives, and 0.168 for dyslipidemia drugs. 42 Antipsychotic medications are among the therapy classes with the fastest-growing use rates in children and teens. Olfson et al. (2006) analyzed data from the NAMCS from 1993 to 2002 to assess rates of treatment with psychotropic drugs in office visits made by children and youth aged 0 to 20 years. 43 Expressed per 100,000 population, the rate of visits that included prescription of an antipsychotic medication increased from 274.7 in 1993-1995 to 1,438.4 in 2002-an astonishing 424% increase in less than a decade. From 2000-2002, of visits at which an antipsychotic was prescribed, only 14.2% were for a diagnosis of psychotic disorders; 37.8% were for disruptive behavior disorder, 31.8% for mood disorder, 3.3% for tic disorder; 17.3% for developmental disorder, and 32.1% for another mental disorder. In addition, stimulants were prescribed at 44.2%, antidepressants at 33.7%, and mood stabilizers at 37.2% of visits at which an antipsychotic was prescribed to a patient aged 20 years or younger. 43 Similarly, in an analysis of NAMCS and NHAMCS  31 The greatly expanded use of narcotics has come at the cost of diversion and abuse due to increased drug supply, 32-34 leading to rapidly escalating rates of deaths due to overdose. 35,36 Deaths from all drugs, including both prescription and "street" drugs (e.g., cocaine, heroin) increased from 9.9 to 12.6 per 100,000 population from 2003 to 2007, 36 and in 2007, opioidrelated deaths outnumbered cocaine-related deaths by 1.93:1 and heroin-related deaths by 5.38:1. 37 Recent news reports suggest that the efforts of the maker of oxycodone CR (Oxycontin) to reduce diversion by making the drug abuse-resistant have increased interest in other drugs, including oxymorphone ER (Opana). 38 Analysis of Drug Abuse Warning Network (DAWN) data for 2008 indicated that the numbers of emergency room visits for illegal drugs and for nonmedical use of prescription drugs (excluding suicide attempts or unintentional ingestion) in the United States were approximately equal at 1.0 million each. 37 These trends have important implications for managed care in 2 respects. First, the Centers for Disease Control (CDC) recommends that PBMs and other insurance providers "identify patients using opioids for noncancer pain who 1) receive a total of 120 or more morphine milligram equivalents of opioids per day from [2] or more sources; 2) show inappropriate patterns of usage such as multiple prescriptions for the same medications from different providers; or 3) also use a sedative-hypnotic" and "notify the prescribing providers about such patients." 37 Second, in April 2011, the U.S. Food and Drug Administration (FDA) announced the upcoming release of Risk Evaluation and Management (REMS) requirements for manufacturers of extended-release and long-acting opioid medications. 39 The primary focus of the REMS program is education of providers about "proper pain management, patient selection, and other requirements" and education for patients that will include "a medication guide that uses consumer friendly language to explain safe use and disposal." 39

Rapidly Expanding Drug Use in Children and Teens
"So young and so many pills" was the description of U.S. children

Medicalization and Prescription Drug Use: International Data
Observations about the medicalization of common human conditions are informed by international comparisons of prescription drug use, but only with several important caveats. These include difficulties in obtaining data from a mix of settings (e.g., hospital vs. ambulatory) and payer types (e.g., public vs. private), 17 and societal differences, such as sick leave policies and health-related behaviors, 49 that can affect medical utilization. Additionally, higher utilization in an international comparison often reflects service delivery differences, such as access to specialists, or therapeutically beneficial access to effective treatments. 50 Nevertheless, there appears to be some useful information in the analyses of prescription drug utilization between countries for specific therapeutic categories and demographic groups.  51 For all persons younger than 65 years, prescription drug use was more common in the United States for antibiotics, statins, and postmenopausal hormones, but use of antiasthmatic drugs was higher in the United Kingdom (16% of females and 18% of males vs. 9% of both females and males in the United States). Although rates of use of antidepressants and antipsychotics were similar in the United States and the United Kingdom for all persons younger than age 65, antidepressants, antipsychotics, and drugs for ADHD were prescribed much more frequently in the United States for persons younger than 20 years. Antidepressants were prescribed more than twice as frequently for children and teenagers in the United States, and the rates of prescribing for ADHD drugs were particularly high in the United States compared with the United Kingdom (e.g., methylphenidate: 2.6% vs. 0.4%, respectively, for males aged 9 years or younger; 13.0% vs. 2.6%, respectively, for males aged 10-14 years; and 8.2% vs. 1.1%, respectively, for males aged 15-19 years). 51 Using more recent data for April 2008 through March 2009, Richards (2010) found that the United States ranked first in the utilization of prescription drugs in 4 of 11 categories analyzed, including atypical antipsychotics and drugs for dementia, respiratory distress syndrome, and rheumatoid arthritis. 17 According to the Organisation for Economic Co-operation and Development (OECD), which measures prescription drug volume as "real pharmaceutical expenditure per capita" by adjusting total prescription drug expense for the average retail pharmaceutical price, the United States is among the nations with the highest prescription drug utilization. 52,53 By this measure in 2005, France and Spain ranked highest at $888 and $828, respectively. The United States, Canada, and the United Kingdom ranked third, ninth, and thirteenth at $792, $589, and $557, respectively, compared with the OECD average of $531. 53 data, Cooper et al. (2006) found an increase in the rate of antipsychotic prescribing per 1,000 U.S. children aged 2 to 18 years from 8.6 in 1995-1996 to 39.4 in 2001-2002 (rate ratio 4.89, 95% CI = 2.50-9.55); 53% of the antipsychotic prescriptions were for behavioral or affective disorders, rather than psychoses. 44 43 Olfson et al. pointed to 2 additional societal trends that may have influenced their findings: (a) decreased use and availability of inpatient psychiatric care, potentially leading to treatment of higher-severity illnesses in outpatients, and (b) "sex differences in size, physical strength, and risk of damage or injury" for male youth, for whom the odds of being prescribed an antipsychotic drug were more than double those of females (OR = 2.3, 95% CI = 1.5-3.7). 43 Exacerbating concerns about the growing use of prescription medications in children is a dearth of information about efficacy, safety, and dosing requirements in this age group. Emerging evidence is raising concerns about the "wide range of metabolic effects" of antipsychotic medications on "individuals who are still growing and developing." 45 A study by Newcomer et al., presented at the June 2011 meeting of the American Society of Clinical Psychopharmacology and not yet peer-reviewed, randomized 125 antipsychotic-naïve children aged 6 to 18 years with symptoms of aggression to treatment with aripiprazole, risperidone, or olanzapine. 46 In an interview with Medscape, Newcomer reported being "actually stunned at how much better they got" but also expressed concerns about results for the study outcome measures, weight and insulin sensitivity. Body fat in the treated children increased by a mean of 8.98% (range = 2%-119%, P < 0.001) and insulin sensitivity decreased by a mean of 2.99 (P = 0.55, critical P value not reported) in just 12 weeks of treatment. 46 The recently launched Pediatric Trials Network (PTN), an initiative of the National Institutes of Health, will address what its director, pediatrician Daniel Benjamin, describes as a "staggering" problem-because only 10% of drugs and devices have been "adequately studied" in children, many therapies prescribed to children are "based on an educated guess by a pediatrician using studies conducted in adults, who often absorb drugs differently or experience different side effects than children." 47 In the next 7 years, the PTN plans to conduct 16 RCTs in "a variety of therapeutic areas;" the first will address the use of lisinopril in pediatric patients following kidney transplantation. 48 poor compliance with therapy and early discontinuation. 56 Osteonecrosis of the jaw, although very rare, is a required part of the "warnings and precautions" on bisphosphonate product labels. 57 Increases in atrial fibrillation in patients randomized to bisphosphonate treatment in clinical trials have been reported; 58,59 however, meta-analyses have produced mixed results. [60][61][62] The FDA announced in October 2010 that the product labeling for all bisphosphonates would be revised to warn of the risk of atypical femur fracture 63 following receipt of at least 300 reports of these events. 64 There is a great deal of national attention in the United States and the United Kingdom on patient safety and avoidable risk associated with potential adverse drug events (ADEs), and the research suggests opportunity to reduce the risk of harm. In recent research, Guthrie et al. (2011) examined the incidence of prescribing of 15 medications defined as high-risk by clinical guidelines that recommended avoidance because of increased risk of harm (e.g., nonsteroidal anti-inflammatory drug [NSAID], tricyclic, or thiazolinedione in patients with heart failure) in a subsample of 139,404 of 1.76 million registered patients (7.9%) who were defined as vulnerable to ADEs because of age, comorbidity, or co-prescription. Of these vulnerable patients, 19,308 (13.9%) received at least 1 high-risk medication. The overall rate of high-risk prescribing for these 15 "avoidable" situations was 1.1% across the population of 1.76 million general medicine outpatients. The highest proportion of vulnerable patients who received the drug to avoid was 50.5% for NSAIDs prescribed in patients aged 75 years or older without gastroprotection (n = 4,464 of 8,840). An atypical antipsychotic was prescribed in 2.8% (n = 288) of 10,171 patients aged older than 65 years with dementia but without psychosis. 65 We have written previously about the widespread efforts in the United States to reduce the use of potentially inappropriate medications (PIMs), including assessment of drugs to be avoided in the elderly (DAE) in the Healthcare Effectiveness and Data Information Set (HEDIS) from the National Committee for Quality Assurance (NCQA). 66 Despite all of the attention to the subject including interventions to reduce the incidence of PIMs and DAEs, there is disagreement among experts regarding definitive criteria to identify inappropriate drug use in which the risks outweigh the benefits. 67

Economic Costs and Benefits of Redefining Treatable Conditions
Objections to the economic costs of expanding indications for pharmacologic treatment are sometimes met with the rejoinder that the medical system should focus on investing in high-value therapies that will prevent disease and, ultimately, produce cost offsets or even cost savings. Notably, this position underpins the waiver of cost-sharing for preventive tests and services for Medicare beneficiaries, which is a major part of the

Expanded Drug Utilization: Consideration of ADEs
In a highly controversial commentary, Moynihan et al. (2002) argued that medicalization of common human conditions occurs primarily because of the corporate interests of pharmaceutical manufacturers. 54 The authors described "disease mongering" as including several phenomena: "turning ordinary ailments into medical problems, seeing mild symptoms as serious, treating personal problems as medical, seeing risks as diseases, and framing prevalence estimates to maximize potential markets." Much of this criticism was transparently identified by the authors as the result of "anecdotal case studies" and "not the result of systematic study." Additionally, despite making several policy recommendations that included "[moving] away from corporate funded information on medical conditions/diseases," the authors noted that they "know little of the extent of these industry funded zones of influence, and even less of their impact," including potentially "unnecessary labeling, poor treatment decisions, iatrogenic illness, and economic waste." 54 However, information pieced together from anecdotes and investigative reporting warrants rigorous investigation to determine the effects of medicalization in specific therapeutic areas.
For example, among the conditions that Moynihan et al. described as inappropriately medicalized was osteoporosis defined by bone mineral density (BMD) values despite low baseline fracture risk and "scientific controversy" over the clinical utility of BMD as a predictor of fracture. 54 Expansion of "pre-osteoporosis" as a disease was investigated by Alonso-Coello et al. (2008), who examined the evidence from 4 post hoc subgroup analyses of patients with osteopenia who had been included in clinical trials of osteoporosis drugs. 55 Alonso-Coello et al. found that in all 4 trials, the relative benefit of drug treatment, measured as percentage reduction in fracture risk, was approximately equal for women with osteopenia or osteoporosis. However, the absolute risk reduction was small. For example, the Discussion section of 1 trial report opened with the mention of a 75% reduction in relative risk but, because the baseline risk of fracture in women with osteopenia is very low, this change represented only a 0.9% absolute (percentage point) risk reduction. 55 Additionally, the authors found that important side effects of the treatments, such as venous thromboembolism, stroke, gastrointestinal effects, and osteonecrosis of the jaw, were either not discussed or given little mention. Alonso-Coello et al. argued that these post hoc analyses contributed to redefinition and expansion of the potential market for osteoporosis drug therapy to more than one-half of white postmenopausal women in the United States. 55 Many of the potential harms associated with osteoporosis drug therapy are well recognized, such as irritation of the upper gastrointestinal mucosa with the oral bisphosphonates and the consequent instruction not to lie down for 60 minutes after oral administration of bisphosphonates, contributing to risk. Yet, estimated costs of prevention with pharmacotherapy were high even prior to the diagnostic changes. Kahn et al. estimated in 2008 that over a 30-year time horizon, application of 11 guideline-recommended CHD prevention strategies would save approximately $904 billion in medical costs-but at a cost of approximately $8.5 trillion, primarily for prescription drug therapy and associated laboratory tests, for a net cost of approximately $7.6 trillion. 70 In considering the economic costs and benefits of pharmacologic treatments, it is worth noting that cost-effectiveness analyses sometimes employ overly optimistic assumptions that are later refuted if subjected to analyses of real patient outcomes. Editorialists Järvinen et al.  72 Using the RCT data, the estimated cost of preventing an adverse gastrointestinal event was approximately $16,000-$20,000. However, results changed when UKGPRD data reflecting use in actual clinical practice, such as the long-term daily use of NSAIDs and COX-2 inhibitors by "only a minority" of patients in contrast with the RCT requirements of continuous use for 6-9 months, were incorporated into the model. The estimated cost to prevent 1 gastrointestinal event was $104,000, and the estimated cost to prevent 1 gastrointestinal hospitalization was $298,000. 72 Fairman and Motheral reached similar conclusions after replacing the assumptions in a widely cited model of Helicobacter pylori eradication with claims database information about actual practice patterns. 73 In the original model, the brand-drug combination of a proton pump inhibitor (PPI) with clarithromycin (PPI-C) was the most cost-effective option at an estimated cost of $980 per effectively treated patient (defined as absence of retreatment with the same or another regimen), compared with estimates of $1,001 for the combination of bismuth, metronidazole, and tetracycline (BMT) and $1,730 for PPI with amoxicillin (PPI-A). In the revised model after empirical adjustment, costs per effectively treated patient for PPI-C, BMT, and PPI-A were $1,118, $852, and $1,131, respectively.
Pharmacoeconomic modeling may become an increasingly important tool in managed care decision making as treated populations expand to include lower-risk patients. If so, examination of model assumptions, rather than sole reliance on model findings, will be vital to making sound choices.
Centers for Medicare & Medicaid (CMS) initiative to reduce the costs of Medicare. 68 In a June 2011 press conference, CMS officials asserted that increasing the use of preventive care "could save about two-thirds of the $2 trillion spent treating preventable chronic illness." 68 However, systematic analyses of costs for screening and prevention versus medical cost offsets have generally shown the opposite to be true. That is, few preventive measures, including Haemophilus influenzae type b vaccination of toddlers, one-time colonoscopy screening for colorectal cancer in men aged 60 to 64 years, 69 and smoking cessation, 70 result in cost savings; and comparisons of costs per quality-adjusted life year (QALY) for a variety of interventions have suggested approximately equal cost-effectiveness for prevention and treatment. 69 A brief review of the subject by Cohen et al. (2008) using the Tufts-New England Medical Center Cost-Effectiveness Registry based on studies through 2005 found that "although some preventive measures do save money, the vast majority reviewed in the health economics literature do not." 69 Additionally, some of the free screening services now being offered to Medicare beneficiaries, such as an annual wellness examination and BMD scans, will lead to the initiation of pharmacotherapy. To date, studies of primary prevention with pharmacotherapy have suggested that it greatly increases net cost, with only small offsets in avoided medical cost and varying degrees of medical benefit, depending on baseline risk level. For example, a transparent decision analytic model by Kahn et al. (2008) based on NHANES IV data applied to the U.S. population in 2005, assessed the economic effects of a variety of guideline-recommended preventive therapies after accounting both for increased medical and prescription drug expenditures and decreases in medical costs because of avoided adverse events (e.g., MI, stroke). 70 None of the pharmacologic strategies was cost-saving, although providing aspirin to individuals at high risk of CHD was nearly cost neutral at $2,779 per QALY. Kahn et al. estimated that lowering BP to less than 140/90 mm Hg in persons without diabetes would cost an estimated $52,983 per QALY; lowering FPG to less than 110 mg per dL would cost $17,478 per QALY; and lowering LDL-C to less than 160 mg per dL in those at low risk of CHD would cost $272,061 per QALY. 70 Notably, all 3 of these treatment goals are higher than those established in the new disease guidelines highlighted by Kaplan and Ong; therefore, the number of treated patients using current guideline standards exceeds the patient counts assumed by Kahn et al.
The higher thresholds have important cost implications. The potential for medical cost offsets is greater in patient populations with higher baseline risk (e.g., secondary prevention or those with numerous CHD risk factors). 69 Thus, the trend toward higher pharmacy costs with minimal medical cost offsets will only escalate as the pool of treated patients expands to include those with lower baseline levels of medical

Clinical Implications of Redefining Conditions as Treatable
In addition to an absence of evidence to support rosy assumptions about the economic effects of the expansion of indications for treatment, arguments in favor of expanding pharmacologic treatments in primary prevention ignore a fundamental problem in our knowledge base about preventive drug therapy: we know little about the clinical benefits and risks of exposing relatively healthy individuals to decades of medication intake. 74 We do know that the risks of adverse effects of newer medications are not fully known at the time of market launch, and that the effects of numerous commonly used drugs are less well understood in children than they are in adults. We also know that evidence about the clinical benefit of pharmacotherapy in primary prevention is limited. Finally, we know that expanded use of prescription drugs can facilitate abuse and diversion, leading to untoward consequences including unnecessary deaths.
In short, what we know about the clinical effects of medicalization of human life is much less than what we don't know, and the list of "knowns" seems to warrant caution and even humility. American society loves to find-or at least think that it has found-"magic bullets" derived from "science" for every conceivable physical, emotional, or societal ill. Yet, medicalization of life may be producing new threats to health, violating the Hippocratic credo to "first, do no harm."